Effectiveness of Tetrahedral Adducts as Transition-State Analogs and Inhibitors of the Class C β-Lactamase of Enterobacter cloacae P99

Abstract

Previous studies have shown that β-lactamases are inhibited by boronates and phosphonates, both of which form covalent tetrahedral adducts with the active-site serine residue. These have been interpreted, as have similar complexes formed with serine proteinases, as transition-state analog structures. Not all molecules capable of forming such tetrahedral adducts are good inhibitors of serine β-lactamases, however. In this paper, a series of molecules potentially capable of forming anionic tetrahedral adducts at the active site [PhCH2CONHCH2M(XY)-OSer] have been assessed as sources of transition-state analogs and as inhibitors of the class C β-lactamase of Enterobacter cloacae P99. It was found by experiment that the aldehyde, the silanetriol, and the α-keto acid (and its methyl ester) of the series were significantly poorer inhibitors than the structurally analogous boronate. This result was explored computationally. From the starting point of the crystal structure of a phosphonate adduct (Lobkovsky et al....